Kingdom-wide structurally similar pathogen effectors target common host factors

Phytopathogens, including bacteria, fungi, and oomycetes, manipulate host immunity by secreting diverse effectors.Due to the evolutionary divergence of pathogen species and the rapid evolution of effectors, functional relationships between effectors may be concealed at the sequence level.Here, we analyzed the structural models of 2,198 effectors from nine fungal, four oomycete, and three bacterial pathogens infecting Solanum lycopersicum.Effector clustering was performed based on both sequence and structural similarity using MMseqs2 and Foldseek, respectively.Among the 81 sequence-unrelated structurally similar (SUSS) effector clusters, five clusters comprised effectors from bacteria, fungi, and oomycetes.Protein-protein interaction assays revealed that XopAU, XopAU-like oomycete effectors (XOE) 1, XOE2, and the XopAU-like fungal effector 1 (XFE1) interacted with SlMKK2, a known host target of XopAU.In addition to identify common host factors targeted by SUSS effectors, we developed an in silico screening strategy using RFdiffusion and AlphaFold-Multimer.Total 34 tomato binder-like proteins (BLPs) were selected as common host factor candidates.Yeast two-hybrid assays validated interactions between BLPs and effectors.Our structure-based study demonstrates that the rapid advancement of AI-based protein structure prediction can be served as a powerful strategy for unveiling host-pathogen interactions.